Parathyroid hormone-related protein (PTHrP), and its receptor, parathyroid hormone receptor 1 (PTH1R), expressed in almost every tissue including the beta cell, are required for life. Studies from our group and others, convincingly demonstrate that PTHrP improves beta cell survival, function and proliferation in rodent islets in vitro. Furthermore, we show that PTHrP has similar salutary effects in vivo, when overexpressed in beta cells of transgenic mice using the rat insulin II promoter (RIP). The RIP-PTHrP transgenic mice display islet hyperplasia, enhanced beta cell proliferation, survival, and function, with resultant hyperinsulinemia and mild hypoglycemia. Our recent data indicate that acute in vivo administration of the amino-terminal region of PTHrP(1-36), the ligand for the PTH1R, has salutary effects on beta cell function, proliferation and beta cell mass in normal mice. Most importantly, PTHrP enhances human beta cell proliferation and improves human beta cell function. However, despite the multiple positive effects of PTHrP on the beta cell, there is very little known regarding the mechanisms and signaling pathways through which PTHrP mediates its beneficial effects; or the physiological role of PTHrP signaling on normal beta cell growth and function; or how these favorable effects of PTHrP could be harnessed therapeutically to enhance islet function, proliferation, and survival. These are important issues that need to be addressed in the field of beta cell biology. This is especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes. Based on our data we hypothesize that PTHrP mediates its manifold salutary actions on the beta cell through distinct signaling pathways, that PTHrP-PTH1R signaling in the beta cell is important for beta cell growth and/or function either in basal and/or stress-induced conditions, and that these multiple positive effects of PTHrP on the beta cell can be harnessed therapeutically. Therefore, we will address these goals with the following Specific Aims: 1) To identify the signaling pathway(s) through which PTHrP enhances beta cell function, proliferation, and survival in vitro. 2) To establish the physiological role of PTH1R signaling in beta cell growth, function and survival in vivo. 3) To examine the role of PTHrP in islet transplant outcomes. Results from these studies should provide a better understanding of how PTHrP, a beta cell growth factor holding immense promise, mediates its beneficial effects on the beta cell, whether its therapeutic potential can be harnessed to improve islet growth and function in the context of islet transplantation, and in the future for regeneration of endogenous beta cells, in the prevention and cure of diabetes. PUBLIC HEALTH RELEVANCE: Studies from our lab and others have shown that parathyroid hormone-related protein (PTHrP) holds immense promise as a beta cell growth factor since it enhances function, proliferation, and survival of beta cells. Studies from the current proposal will unravel the mechanisms by which this growth factor mediates its beneficial effects in the beta cell both under normal conditions as well as under pathophysiological conditions of type 1 and type 2 diabetes. This will enable us to identify suitable molecular targets to improve islet growth and function for future therapeutic studies. Most importantly, these studies will examine whether the salutary effects of PTHrP on the beta cell can be harnessed therapeutically to improve islet transplants. These studies are especially critical given the current worldwide diabetes epidemic, the advent of islet transplantation as a treatment for diabetes, the current paucity of available islets for transplants, and the need to further enhance the growth and function of endogenous beta cells for the future cure or prevention of diabetes.